A session with UK experts Robin Sanderson and Tobias Menne, who discuss lymphoma treatment in the UK, drawing focus on CAR-T therapy.

Welcome to The Lymphoma Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Robin Sanderson and Tobias Menne, who discuss lymphoma treatment in the UK, drawing focus on CAR-T therapy.

In this session, our experts will discuss recent updates in lymphoma treatment, the management of CAR-T toxicity, the ZUMA-7 and TRANSFORM trials, and how to manage the delivery of CAR-T therapy in the UK.

Real-world data and the management of CAR-T toxicity

 

“What’s really reassuring about all the real-world data now is that we can manage CAR-T toxicity safely. And that’s what’s so different compared to the beginning of the program when we were all learning. And now, I feel very comfortable talking to a patient about CAR-T toxicity and the things that we would do, and confident that we would be able to control it.”

– Robin Sanderson 

Managing patients who are transplant-ineligible

 

“I think this is where you probably need to still be better in selecting the right patients who you think you will be able to bridge, and then get to the transplant.”

– Tobias Menne

“I think the message to refer is really, there is definitely this transplant ineligible, CAR-T eligible group. And if there’s a question about whether they think patients are fit enough, then we’re happy as CAR-T physicians to receive patients early and to help guide people down that pathway if we think it’s appropriate.”

– Robin Sanderson

 

Clinical trial updates: ZUMA-7 and TRANSFORM

 

“I think the ZUMA-7 data looked certainly promising in the PFS. There is a significant difference in PFS and EFS, and which was a primary endpoint. In the overall survival, they did not yet say… Show a clear separation. There was a separation, but this wasn’t yet significant. I think this is something where NICE will look at it, and they need to probably show an overall survival advantage.”

– Tobias Menne

Managing the delivery of treatment in the UK

 

“I mean, we need business cases and we need a bit of service expansion because if all of these CAR-T indications get approved, that is a huge amount more work for us, in a very good way, of course.”

– Robin Sanderson

“And it’s perhaps something we will have to discuss. And NICE and NHS England have to decide if they would ever allow autograft centers to become CAR-T cell centers, because at the moment, a decision was made that only allograft centers can become CAR-T cell centers.”

– Tobias Menne

Full transcript

Robin Sanderson:

Good morning. I’m Robin Sanderson, I’m a CAR-T consultant at King’s College Hospital in London. I’m at BSH and we’re going to talk about CAR-T today.

Tobias Menne:

And I’m Tobias Menne. I’m a consultant hematologist at the Freeman Hospital in Newcastle. And I’m the CAR-T cell lead.

Robin Sanderson:

So, I think we’re going to talk about the CAR-T session we had yesterday. There was some presentation of some French and some UK data. We discussed the most recent ASH publication, ASH abstract from the UK data where we talked about CAR-T toxicity.

It’s always interesting to see the readout from the real-world data series now. I think we could be proud of the UK data series; the outcomes look good. But also the toxicity, from my perspective is really very interesting. We’re seeing a lot less real-world toxicity than we were expecting, which is what I think we see in our clinical practice. But it’s also interesting to explore the use of anakinra and the fact that steroids does not affect overall survival and progression-free survival in our cohort. What did you think of the DESCAR-T data that was presented?

Tobias Menne:

I think it was actually very interesting. And Steve Le Gouill presented [inaudible], and who’d started the study, and he presented the data, which he already had presented at ASH. And there’s now some additional updates also from Emmanuel Bachy and they have done, initially looked just at axi-cel and tisagen cohorts, but kept them separate. But then they did further analysis propensity, the score analysis, which is kind of best way of trying to compare them directly, because obviously there will be never a phase III study comparing tisagen with axi-cel. And they could show that if you use axi-cel, you had improved PFS, but now also overall survival, advantageous compared to tisagen, but there was increased toxicity. There was increased rates of patients who developed cytokine release syndrome, neurotoxicity, and also grade 3 cytokine release syndrome and grade 3 neurotoxicity.

So you have to always accept this. If you consider giving a patient axi-cel, there’s a higher chance of getting significant toxicity compared to tisagen. But overall, you appear to get an improved PFS and overall survival, including in patients who are above 70, up to age of 75 on further sub-analysis. In their cohort of nearly 500 patients, they now treated on commercial product. So I think that’s quite informative. And it’s obviously also something we’ve seen from your data that… It’s quite clear that if you compare tisagen and axi-cel, there’s a difference in toxicity.

Robin Sanderson:

Yeah, definitely.

Tobias Menne:

And your data looked very interesting in a way how we now manage them compared to the original data. What do you think is the main reason why our toxicity has improved?

Robin Sanderson:

I mean, we’re obviously giving a lot more steroids, aren’t we, I think compared to the pivotal clinical trials. And we don’t see toxicity from CAR-T death, or we don’t see cerebral edema and these sorts of things, but we see different sorts of problems. The non-relapse mortality post axi-cel is… It’s interesting because there’s a lot of infections and I think some of the complications probably do relate to steroids. So, I think we are much better at controlling CAR-T toxicity. But steroids, as we all know, have their own side effects. But it’s also reassuring that that does not pan out as a problem with the… Our overall survival and progression-free survival data.

What’s interesting about the French set up is just how… Well the set up they actually have in France for collecting the data, and how much help they get doing it. I mean, it would be great if we had-

Tobias Menne:

Absolutely. This is something I only realized in the last six months; they have their own CRO which runs all their studies for the lymphoma group in France. And they actually have 200 people, monitors, data manager, finance people. So they’re running their studies. And so the DESCAR-T study is… A study run by them, financed by the companies where they look, and they include every patient because one of the requirements is if you give CAR-T cells to the patients, they need to be registered onto the study… And get really high quality data. They have extra monitors going out monitoring 30% to 50% of all the clinical notes. So the data are just like a proper study. And so the data they have are just brilliant… And really informative. And this is why they’re able then to do this kind of propensity score analysis, because they have all the important parameters to use.

And that’s something we probably should learn from and think about how we can potentially copy them in the future. I think that’s very important. In regards to toxicity, I think the other thing is… When I started, I can remember, I was scared to give tocilizumab until they were already close to grade 3, because I was always worried that you might interrupt T-cell expansion, but I think we got a bit better in realizing actually it’s not as important. And you can start to give tocilizumab earlier. You don’t need to wait until they’re close to getting grade 3s. And so we started to give at typically grade 2s, but much earlier grade 2s. And we have given it also during COVID times for grade 1 patients. When do you nowadays give it?

Robin Sanderson:

So generally grade 2, but yeah, I feel quite reassured now in giving it even grade 1 in patients who are.. Who have lots of comorbidities. I mean, what’s really reassuring about all the real-world data now is that we can manage CAR-T toxicity safely. And that’s what’s so different compared to the beginning of the program when we were all learning. And now, I feel very comfortable talking to a patient about CAR-T toxicity and the things that we would do, and confident that we would be able to control it.

Tobias Menne:

Exactly. And I think… You have nowadays a field of patients who are… Who potentially could die from the procedure, the ones who have… With lots of tumor burdens. And so there, we often go in earlier because we know that they will… If you don’t stop the CRS going completely haywire, you need to go in earlier with… Tocilizumab, steroids when they have already grade 1, grade 2s. And I think this is how we’re preventing nowadays people going into intensive care unit and people dying from the procedure.

Robin Sanderson:

Yeah, because the cohorts, when we looked at the NCCP national toxicity cohort, one of the interesting findings for me is we identified real-world risk factors for severe toxicity. So they would be a poor performance status, a high LDH on infusion day, and people who are progressing through bridging. These to me are just simple, useful ways of identifying high-risk patients for CAR-T toxicity. And they’re also the same risk factors for people that don’t do very well with CAR-T itself. So those patients, yeah, there’s probably a bit to work on, on how we get the highest risk, the sickest patients through. But it’s just useful having these clinical tools just be able to identify certain patients.

Tobias Menne:

Absolutely. And I think the pathway has changed. We started also to use more anakinra and I know you have done it as well. So when we have two or three doses of tocilizumab, we start to go in with anakinra. We notice that if you give three or four doses, there’s not really a significant difference. So we start to use anakinra a bit earlier. And I don’t know if this is helping or not. I mean, there’s not a clear evidence. But obviously in your cohort, there was 20 or 30 patients.

Robin Sanderson:

Yeah, the national cohort, yeah, there’s quite a lot. But obviously, we haven’t looked at it in a trial; we’re just sort of looking back. But yeah, certainly there’s a lot of anakinra experience in the UK now, and that seems to be helpful. But yeah, it hasn’t been put together in a trial format.

Tobias Menne:

And there was an interesting study published at ASH where they used anakinra-

Robin Sanderson:

As prophylaxis, yeah.

Tobias Menne:

As prophylaxis, and it looks potentially promising, and you can see how it could help. And perhaps in the future, we might use anakinra much earlier than-

Robin Sanderson:

And I suppose the appeal of it is it’s sort of like a steroid sparing agent, isn’t it? Even that in principle seems to be appealing to me.

Tobias Menne:

And it’s subcut, it’s much cheaper than tocilizumab.

Robin Sanderson:

Yeah, it’s a lot more.

Tobias Menne:

So there’s a lot of things why it could become, perhaps in the future, the thing and probably more… We need more studies. So this is what’s very interesting. There was also very interesting talk from Andrea Kuhnl on patients who we would regard frailer, not fit for transplant. And I thought these data were very interesting obviously that come from your trust. What did you think about them?

Robin Sanderson:

Yeah. Again, it’s sort of reflecting what we’ve been doing in clinical practice, that we’ve been pushing CAR-T to an older age range. And that actually, they do have a very good outcome. But I think what she highlighted was if you get to in… If these sort of patients get to infusion… They have a good chance of doing as well as you would hope. But there was a higher drop off in patients getting to infusions. So that period of time, bridging is obviously very crucial, isn’t it?

Tobias Menne:

No, absolutely. And I think this is where you probably need to still be better in selecting the right patients who you think you will be able to bridge, and then get to the transplant. But the outcome data for those who were… Did not transplant and had the CAR-T cells were identical really. The graphs didn’t really look significantly different to the cohort which we would regard as fit. So I think this is very promising and I think this is.. With real-world data now everywhere that you can give CAR-T cells to a 75-year old patient. Potentially, you even can give it up to patients of 80 years as long as they are fit enough.

Robin Sanderson:

Yeah, we’ve gone up to 81 and it’s obviously a very selected group.

Tobias Menne:

Yeah.

Robin Sanderson:

But yeah.

Tobias Menne:

Our oldest is now 79, and then we have two, another at 76, so you can do it. But you need to be careful about this one. They need to be relatively fit.

Robin Sanderson:

So, I think the message to refer is really, there is definitely this transplant ineligible, CAR-T eligible group. And if there’s a question about whether they think patients are fit enough, then we’re happy as CAR-T physicians to receive patients early and to help guide people down that pathway if we think it’s appropriate.

Tobias Menne:

Yeah…. Absolutely. What we actually tell all our referring centers, if a patient is fit enough for R-CHOP and tolerated R-CHOP reasonably well, they should be fit enough for CAR-T cells.

Robin Sanderson:

Yeah, absolutely.

Tobias Menne:

I mean this kind of idea that they need to be transplant eligible, and then be able to go through transplant is not really the case. Patients do have significantly less serious toxicity, I would say.

Robin Sanderson:

Yeah. And one discussion that I feel like you have in MDTs a lot is with elderly patients, should you give them R-CHOP or R-mini-CHOP. And now I say, well, you have to give them a R-CHOP if you anyway want to consider them for further therapies later on, because we know that that’s an eligibility criteria as part of the national CAR-T panel sets it. So in a way, that’s quite helpful advice to give to referrers. It’s a reason to give full dose R-CHOP.

Tobias Menne:

Yeah. No, absolutely. We normally would always give R-CHOP to everyone… Below 80, R-mini-CHOP normally for the above 80s. But we have started to give some R-CHOP in case [inaudible]..

Robin Sanderson:

To keep options open.

Tobias Menne:

Keep options open, exactly. I think that is very important. And obviously, we have now established that we can deliver CAR-T cells and we can deliver it across the country, and we need to get all patients really referred to the appropriate CAR-T cell center as soon as possible. And there will be more CAR-T cell centers opening in the future.

Robin Sanderson:

Yeah.

Tobias Menne:

So there’s quite a lot of things happening in the CAR-T cell world and in the lymphoma world. We’ve seen now the ZUMA-7 data, which were presented at ASH. What is your feeling about CAR-T cells using in second-line treatment once they have failed R-CHOP chemotherapy?

Robin Sanderson:

I mean, personally, I’m keen. I feel like particularly these high-risk patients, like the primary refractory to R-CHOP, obviously we go through salvage and we go through the appropriate steps at the moment, but it just feels sometimes a bit like we’re going through the motions just to get them to CAR-T. I just can’t really think of many patients who were primary refractory to R-CHOP that ended up having an autograft in my recent practice. So why not bring it forwards if the data is good? Which I think it is, but-

Tobias Menne:

Yeah. I think the ZUMA-7 data looked certainly promising in the PFS. There is a significant difference in PFS and EFS, and which was a primary endpoint. In the overall survival, they did not yet say… Show a clear separation. There was a separation, but this wasn’t yet significant. I think this is something where NICE will look at it, and they need to probably show an overall survival advantage. Because they could argue, otherwise you can always give CAR-T at the third line. But the curves are separating, so I wouldn’t be surprised if they do a follow-up. There will be separation. And at the same ASH meetings, there was also a proof of concept with a different construct called liso-cel, which showed… the TRANSFORM study, which showed the same thing. And there, the overall survival is already separating quite clearly. So I think in the… I cannot see that in the future, I would assume that at some point-

Robin Sanderson:

We’ll be doing it, yeah.

Tobias Menne:

We will do it, and it will become second-line treatment. And the CAR-T cells will just become the standard second-line salvage treatment. When exactly it’s not clear, I think that England is discussing it. NICE is discussing it, in summer. And they expect a decision in September, I think.

Robin Sanderson:

Yeah, it’s later in the year, yeah.

Tobias Menne:

So probably potentially beginning of next year, we might be able to give CAR-T cells as a second-line treatment.

Robin Sanderson:

I suppose it’s important to highlight. It’s not all second-line patients, is it?

Tobias Menne:

Yeah.

Robin Sanderson:

It’s people who relapse within… A primary refractory or relapsed within 12 months. So I think, the lymphoma-

Tobias Menne:

12 months after they completed the treatment.

Robin Sanderson:

So is it 12 months after completion, yeah. I was this [inaudible 00:13:58].

Tobias Menne:

This is what’s in the study, because the [inaudible] data looked at 12-month outcomes after diagnosis, where they showed that people within 12 months did significantly worse than those who had relapsed after 12 months. But in TRANSFORM and… Actually, it’s 12 months after they completed the R-CHOP chemotherapy. So in fact it’s one and a half years from the time of diagnosis, which is the majority of patients. If you relapse, you typically will relapse in the first one and a half years. So it would completely change the way we would not use autografts anymore, except for those who relapse later on.

Robin Sanderson:

Yeah.

Tobias Menne:

And I think this will be interesting. And it’s not just CAR-T cells in DLBCL, but we obviously… Mantle cell has been approved, but follicular lymphoma is due to be discussed at NICE.

Robin Sanderson:

Yeah. And Tecartus in ALL is also due to be discussed this year.

Tobias Menne:

Yeah, and Tecartus in ALL, this year. There’s a lot of things happening where commercial might become available. And then obviously, the big one is myeloma, which is also discussed this year. If myeloma becomes available, then we might have problems with capacity. How do you think we will be able to manage if all these indications get approved? How would we be able to deliver this treatment in the UK?

Robin Sanderson:

That is a very good question, isn’t it? I mean, we need business cases and we need a bit of service expansion because if all of these CAR-T indications get approved, that is a huge amount more work for us, in a very good way, of course.

Tobias Menne:

Yeah, that’s right. And then, I was fascinated by the French that they currently have 36 centers already running as CAR-T cell centers. And France has the same population as we have, and we currently have 12 centers.

Robin Sanderson:

Yeah, oh yeah. I didn’t think about-

Tobias Menne:

And we only have another 12 potential centers, the allograft centers who could… So we could go maximum up to 24 centers.

Robin Sanderson:

But we still won’t be at that number then, yeah.

Tobias Menne:

It will be very difficult. And the French, this was very interesting, they also allow autograft centers to become CAR-T cell centers. And it’s perhaps something we will have to discuss. And NICE and NHS England has to decide if they would ever allow autograft centers to become CAR-T cell centers, because at the moment, a decision was made that only allograft centers can become CAR-T cell centers.

Robin Sanderson:

I suppose there’s challenges with the quality in JC and all these sorts of things, it’s not just straightforward to just start, is it? There’s lots of things you need to be able to do.

Tobias Menne:

Yeah, you need to do this and that’s something. JC needs to go through the process. They need to be approved and that’s something. But I think it’s absolutely fascinating. Obviously, the big interesting story, which is not yet for me clear and that’s no one here knows this, how bispecifics will affect the management of lymphoma patients, and that’s something-

Robin Sanderson:

Yeah, it’s something unknown, isn’t it? And Andrew MacMillan, the chair, he asked that question, didn’t he, to stick to Steve? You can’t really answer the question, because there’s no… Head to head. So it’s going to come down to a clinical judgment at the end, isn’t it?

Tobias Menne:

Yeah. I think it will take some time before they will ever do some direct comparison between CAR-T cells and bispecifics. So I think what will be really crucial that we get really good real-world data from patients treated with CAR-T cells, but also patients treated with bispecifics. And that based on this one, you can then get… Do some form of comparison to just get a feel, because I think it would be very interesting to figure out the sequencing in the future, how we sequence these different treatments.

Robin Sanderson:

And the UK and France are very well positioned to answer those sort of real-world questions, because the denominator is more accurate, isn’t it? Because we offer these treatments to all of our population. Where I think US real-world series, probably it’s a bit more selected. So, I think that’s an advantage for our sort of data collections.

Tobias Menne:

Yeah. No, absolutely. And I think that’s the beauty with the French, that they insist that everyone gets. So it means also you get good ethnicity covering, which you normally don’t get in trials, to see if they’re as effective in all the different ethnic subgroups. And that’s something… Would really helpful.

Robin Sanderson:

Yeah, I agree.

 

Watch the full session

THE LYMPHOMA CHANNEL

 

EXPLORE THE LATEST UPDATES IN LYMPHOMA, INCLUDING EXPERT INTERVIEWS FROM MAJOR INTERNATIONAL CONGRESSES, PODCASTS AND E-LEARNING.

Disclosures

Robin Sanderson:

Kite – Honoraria, speaker’s bureau
Novartis – Honoraria, speaker’s bureau

Tobias Menne –

Sign-up for our Newsletter!

Keep up to date with all the latest news with our monthly newsletter